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Therefore, we determined the effects of the organic nitrates glyceryl trinitrate (100 \u03bcmol\/L), pentaerythritol tetranitrate (10 \u03bcmol\/L), and isosorbide-5-mononitrate on electrically stimulated contractile response (CR) and cAMP and cGMP content of isolated adult rat ventricular cardiomyocytes compared with different concentrations of the spontaneous NO donors<jats:italic>S<\/jats:italic>-nitroso-<jats:italic>N<\/jats:italic>-acetyl-d,l-penicillamine (SNAP) and 2,2-diethyl-1-hydroxy-1-nitroso-hydrazine (DEA\/NO). A high concentration of spontaneous NO donors (100 \u03bcmol\/L) caused a large increase in cGMP content that was accompanied by a decrease in CR to 73.8\u00b16.7% (SNAP) and 80.9\u00b16.1% (DEA\/NO) of the control values. Inhibition of cGMP-dependent protein kinase by 10 \u03bcmol\/L KT 5822 converted this effect into a pronounced improvement of CR (163.5\u00b114.0%). By contrast, the organic nitrates caused a small but significant increase in cGMP, which was accompanied by an increase in cAMP and CR identical to that induced by 10 nmol\/L isoprenaline (141.6\u00b16.4%). A similar effect was observed with a low concentration (1 \u03bcmol\/L) of SNAP and DEA\/NO. All increases in CR induced by nitrates were abolished after inhibition of cAMP-dependent protein kinase by Rp-cAMPS (10 \u03bcmol\/L). The positive contractile effect of isoprenaline was enhanced by 1 \u03bcmol\/L SNAP. This effect was also demonstrated in isolated rat papillary muscles. These results indicate that in cardiac muscle (1) organic nitrates are bioactivated to NO; (2) this results in a moderate increase in cGMP, which causes an improved CR by increasing cAMP and activating cAMP-dependent protein kinase; and (3) a large increase in cGMP, produced by high doses of NO donors, reduces CR because of the activation of cGMP-dependent protein kinase.<\/jats:p>","DOI":"10.1161\/01.res.78.1.91","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:47:05Z","timestamp":1339462025000},"page":"91-101","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":191,"title":["Low Increase in cGMP Induced by Organic Nitrates and Nitrovasodilators Improves Contractile Response of Rat Ventricular Myocytes"],"prefix":"10.1161","volume":"78","author":[{"given":"Georg","family":"Kojda","sequence":"first","affiliation":[{"name":"From the Institut fu\u0308r Pharmakologie (G.K., K.K., P.N., E.N.), Heinrich-Heine-Universita\u0308t, Du\u0308sseldorf, Germany, and the Institut fu\u0308r Physiologie (K.D.S., H.M.P.), Justus-Liebig-Universita\u0308t, Gie\u03b2en, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Kottenberg","sequence":"additional","affiliation":[{"name":"From the Institut fu\u0308r Pharmakologie (G.K., K.K., P.N., E.N.), Heinrich-Heine-Universita\u0308t, Du\u0308sseldorf, Germany, and the Institut fu\u0308r Physiologie (K.D.S., H.M.P.), Justus-Liebig-Universita\u0308t, Gie\u03b2en, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Nix","sequence":"additional","affiliation":[{"name":"From the Institut fu\u0308r Pharmakologie (G.K., K.K., P.N., E.N.), Heinrich-Heine-Universita\u0308t, Du\u0308sseldorf, Germany, and the Institut fu\u0308r Physiologie (K.D.S., H.M.P.), Justus-Liebig-Universita\u0308t, Gie\u03b2en, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus Dieter","family":"Schlu\u0308ter","sequence":"additional","affiliation":[{"name":"From the Institut fu\u0308r Pharmakologie (G.K., K.K., P.N., E.N.), Heinrich-Heine-Universita\u0308t, Du\u0308sseldorf, Germany, and the Institut fu\u0308r Physiologie (K.D.S., H.M.P.), Justus-Liebig-Universita\u0308t, Gie\u03b2en, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans Michael","family":"Piper","sequence":"additional","affiliation":[{"name":"From the Institut fu\u0308r Pharmakologie (G.K., K.K., P.N., E.N.), Heinrich-Heine-Universita\u0308t, Du\u0308sseldorf, Germany, and the Institut fu\u0308r Physiologie (K.D.S., H.M.P.), Justus-Liebig-Universita\u0308t, Gie\u03b2en, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eike","family":"Noack","sequence":"additional","affiliation":[{"name":"From the Institut fu\u0308r Pharmakologie (G.K., K.K., P.N., E.N.), Heinrich-Heine-Universita\u0308t, Du\u0308sseldorf, Germany, and the Institut fu\u0308r Physiologie (K.D.S., H.M.P.), Justus-Liebig-Universita\u0308t, Gie\u03b2en, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0031-6997(25)06667-0","volume":"43","year":"1991","unstructured":"Ahlner J, Andersson RGG, Torfg\u00e5rd K, Axelsson KL. 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